US5770738A - Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions - Google Patents

Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions Download PDF

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US5770738A
US5770738A US08/412,408 US41240895A US5770738A US 5770738 A US5770738 A US 5770738A US 41240895 A US41240895 A US 41240895A US 5770738 A US5770738 A US 5770738A
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tropanyl
epoxy
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Rolf Banholzer
Rudolf Bauer
Richard Reichl
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Boehringer Ingelheim GmbH
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D451/00Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06Oxygen atoms
    • C07D451/10Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Abstract

The new compounds of formula
A--O--CO--Z                                                (I)
(wherein A and Z are defined as explained in the specification) can be prepared by conventional methods; they are suitable as active substances for pharmaceutical compositions.

Description

This is a continuation of application Ser. No. 08/117,199, filed Dec. 2, 1993, abandoned.

The invention relates to new esters of bi- and tricyclic amino alcohols, the preparation of these compounds and their use in pharmaceutical compositions.

The new compounds correspond to the formula

A--O--CO--Z                                                (I)

wherein

A represents the group ##STR1## wherein m represents 0, 1 or 2,

n represents 1 or 2 and m+n<3,

Q represents one of the double-bonded groups --CH2 --CH2 --, --CH2 --CH2 --CH2 --, --CH═CH--, ##STR2## or --CH2 --Q"--(CH2)p --(p=0 or 1) and

Q' represents the group ═NR, the group ═NRR' or the group CH2, wherein R represents an optionally halo- or hydroxy-substituted C1-4 -alkyl group, R' represents a C1-4 -alkyl group and R and R' together may also form a C4-6 -alkylene group, and, in the case of quaternary compounds, an equivalent of an anion (X.sup.θ), is associated with the positive charge of the N-atom, and

Q" has the same meanings as Q', with the exception of CH2, and with the proviso that Q represents --CH2 --Q"--(CH2)p -- when Q' represents CH2,

Z represents the group ##STR3## wherein R1 represents H, OH, CH2 OH, C1-4 -alkyl or C1-4 -alkoxy,

R2 and R3, which may be identical or different and one of which may also be H, represent

(a) phenyl, furyl, an aromatic group which is isoelectronic with thienyl, C5-7 -cycloalkyl, pyridyl, C5-7 -cycloalkenyl or, in particular if m is equal to O and/or Q is equal to --CH2 --Q"--(CH2)p, R2, may also represent thienyl,

(b) an aliphatic group having up to 20 carbon atoms optionally interrupted by oxygen, or a C1-6 -alkyl group substituted by phenyl, phenoxy, thienyl, furyl, C5-7 -cycloalkyl or fluorine,

(c) the entire group III may also represent the tricyclic group of the formula ##STR4## or a group of formula ##STR5## wherein B may represent S or CH═CH, R'1 has the same meaning as R1 and may additionally represent phenyl, thienyl, furyl, thiazolyl, thiadiazolyl or methoxyphenyl, Y represents a single bond, an O- or S-atom or one of the groups --CH2 --, --CH2 --CH2 --, --CH═CH--, --OCH2 -- or --S--CH2 -- and q represents 1, 2 or 3.

In the compounds of formula I R2 preferably represents OH. The group --OA preferably has an α-configuration and is derived for example from scopine, tropine, granatoline or 6,7-dehydrotropine or the corresponding nor-compounds; --OA may, however, also have the β-configuration as in pseudotropine or pseudoscopine.

Examples of corresponding groups include: ##STR6##

The substituent R is preferably a lower alkyl group, especially CH3, or may also represent, for example, C2 H5, n-C3 H7, i-C3 H7 and R' preferably represents CH3. R and R' together may represent, for example, --(CH2)5 --. The halogen substituent for R is preferably F or, to a lesser extent, Cl. If R represents a halo- or hydroxy-substituted alkyl group it is preferably --CH2 --CH2 F or --CH2 --CH2 OH. Accordingly, the group A represents, for example, the groups of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, N-β-fluoroethylnortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary compounds, the anion preferably being Br.sup.θ or CH3 So3.sup.θ.

The group Z may have the following meanings, for example, whilst the aromatic groups may also be substituted, e.g. by CH3, OCH3, F or Cl: ##STR7##

If in the group II m represents O and/or Q represents --CH2 --Q"--(CH2)p --, the group III may have the following additional meanings, in particular: ##STR8##

The quaternary compounds of formula I are particularly suitable for therapeutic use, while the tertiary compounds are important not only as active substances but also as intermediate products.

The compounds according to the invention are anticholinergics with a potent and long-lasting effect. At dosages in the microgram range, periods of effect of more than 24 hours are achieved after inhalation. Moreover, the toxicity is in the same range as that of the standard commercial product ipratropium bromide, whilst at the same time the therapeutic effect is in some cases significantly greater.

In accordance with their nature as anticholinergics, the new compounds are suitable, for example, for treating chronically obstructive bronchitis and (slight to moderate) asthma and also for treating vagally induced sinus bradycardia. Whereas in diseases of the respiratory tract it is chiefly recommended to administer the new active substances by inhalation (especially the quaternary compounds), thereby largely eliminating any side effects, the compounds are preferably administered by intravenous or oral route in the case of sinus bradycardia. It has been found to be advantageous that the new compounds have virtually no effect on gastrointestinal motility.

For use, the compounds according to the invention are processed with known excipients and/or carriers to form conventional galenic preparations, e.g. solutions for inhalation, suspensions in liquefied propellant gases, preparations containing liposomes or proliposomes, injectable solutions, plain or coated tablets, capsules, powders for inhalation for use in conventional inhalers.

Examples of formulations (amounts given in percent by weight):

1Metering aerosol

______________________________________Active substance according to                    0.005the inventionSorbitantrioleate        0.1Monofluorotrichloromethane and                    to 100difluorodichloromethane 2:3______________________________________

The suspension is poured into a conventional aerosol container with a metering valve.

Preferably, 50 μl of suspension are dispensed on each actuation. The active substance may also be dispensed in a higher dosage if desired (e.g. 0.02% by weight).

2. Tablets

______________________________________Active substance according to               0.05the inventionColloidal silica    0.95Lactose             65.00Potato starch       28.00Polyvinylpyrrolidone               3.00Na-cellulose glycolate               2.00Magnesium stearate  1.00______________________________________

The ingredients are processed in the usual way to form tablets weighing 200 mg.

The advantageous properties of the new compounds are found for example in their inhibition of broncholysis in rabbits (acetylcholine spasm i.v.). After intravenous administration of the new active substances (dosage 3 μg/kg i.v.) the maximum effect was obtained after 10 to 40 minutes. Even on isolated organs, e.g. on the guinea-pig ileum or rectum, numerous compounds according to the invention were found to have a long duration of activity.

The new compounds may be prepared by methods known per se.

1. Preferably an ester of formula

Z--CO--OR"                                                 (VII),

wherein Z is as hereinbefore defined and R" represents a C1-4 -alkyl group, preferably methyl or ethyl, is transesterified, in the presence of a conventional transesterification catalyst, with an aminoalcohol of formula ##STR9## wherein m and n are as hereinbefore defined, Q'a represents NR' or NH, Qa has the same meaning as Q, with the proviso that if Qa represents --CH2 --Q"--(CH2)p --, Q" can only represent NR', and wherein the OH-group is in the α- or β-position, or

2. a reactive derivative (R'" represents a readily cleavable group)

Z--CO--OR"'                                                (IX)

of the acid Z--CO--OH, particularly an acid chloride or imidazolide thereof, is reacted with an alcohol of formula VIII, optionally in excess or in the presence of a tertiary amine such as triethylamine, and optionally the resulting compound

a) if Q'a represents NR', is quaternised with a reactive monoderivative X--R of a corresponding alkane (X=leaving group) or

b) if Q' a represents NH, is quaternised with a terminally disubstituted alkane X--(C4-6 -9alkylene)--X without intermediate isolation or

c) if Qa equals --CH2 --NR'--(CH2)p --, is quaternised with a reactive monoderivative X--R.

Alternatively, starting compounds may be quaternised, in which the starting compound VIII contains R representing a "halo- or hydroxy-substituted alkyl group" instead of R' at the nitrogen atom.

The transesterification according to process 1 is carried out with heating in an organic solvent, e.g. toluene, xylene or heptane, or in a melt, using strong bases such as sodium methoxide, sodium ethoxide, sodium hydride or metallic sodium as catalyst. In order to eliminate the lower alcohol released from the equilibrium, reduced pressure is used, and possibly the alcohol is distilled off azeotropically. The transesterification is carried out at temperatures generally not exceeding 95° C. Frequently, trans-esterification proceeds more easily in a melt. The reaction according to process 2 is carried out in an organic solvent or mixture of solvents which is sufficiently inert under the reaction conditions, e.g. acetone or acetonitrile, at temperatures between about 0° C. and the boiling temperature of the reaction mixture.

The free bases may be obtained from acid addition salts of the tertiary amines, if desired, using suitable basic compounds in a manner known per se. The quaternisation is carried out in suitable solvents, e.g. acetonitrile or acetonitrile/methylene chloride, preferably at ambient temperature; the preferred quaternising reagent is a corresponding alkyl halide, e.g. alkyl bromide, or a corresponding sulphonic acid derivative, e.g. a methane- or toluenesulphonic acid derivative. Transesterification products wherein Q' represents NH are used as starting materials for those compounds in which R and R' together represent a C4-6 -alkylene group. Conversion into the tertiary and then quaternary compound is carried out using suitable 1,4-, 1,5- or 1,6-dihaloalkanes without intermediate isolation.

The starting compounds, where they have not already been described, may be obtained analogously to known compounds.

EXAMPLES

Methyl di-(2-thienyl)glycolate from dimethyloxalate and 2-thienylmagnesium bromide;

Ethyl di-(2-thienyl)glycolate from (2-thienyl)glyoxylic: acid and 2-thienyllithium;

Ethyl hydroxyphenyl-(2-thienyl)acetate from methylphenylglyoxylate and 2-thienylmagnesium bromide or from methyl (2-thienyl)glyoxylate and phenylmagnesium bromide.

Similarly, methyl 2-thienylglyoxylate and cyclohexyl- or cyclopentylmagnesium bromide may be reacted.

There are also several possible methods of preparing the aminoalcohols.

Pseudoscopine can be obtained according to M. Polonovski et al., Bull. soc. chim. 43, 79 (1928).

Pseudotropenol can be isolated from the mixture (by fractional crystallisation or distillation) which is obtained, for example, according to V. Hayakawa et al., J. Amer.Chem.Soc. 1978, 100(6), 1786 or R. Noyori et al., J.Amer.Chem.Soc. 1974, 96(10), 3336.

N-ethylnorscopine and N-isopropylnorscopine may be prepared by hydrogenolysis from the corresponding N-alkylnorscopolamines analogously to Banholzer DE-A P 3215933. 6-methyl-6-azabicyclo 3.2.1!octan-3-α-ol can be prepared according to F. I. Carroff et al., J. Med.Chem. 30, 805 (1987), and 7-methyl-7-azabicyclo- 2.2.1!heptan-2α-ol may be obtained according to J. R. Pfister et al., J. Pharmac. Sciences 74, 208 (1985).

Starting from 2- or 3-furylglyoxylnitrile the corresponding methylesters may be prepared in conventional manner via the 2- or 3-furylglyoxylic acid obtainable from the starting material. From these methylesters, the corresponding glycolic acid esters may be obtained as described with the organometallic derivatives of 2- or 3-bromothiophene. The organometallic compounds obtainable from 2-, 3- or 4-halopyridine can be reacted with methyl 2- or 3-thienylglyoxylate to obtain the corresponding glycolic acid esters.

Thienylglycolic acid esters in which the thiophene ring in the 2- or 3-position contains fluorine may be obtained, for example, starting from 2-fluorothiophene or 3-fluorothiophene (bromination to obtain 2-bromo-3- fluoro- or 2-bromo-5-fluorothiophene and, after conversion into corresponding organometallic compounds, reaction with suitable glyoxylic acid esters to obtain the glycolic acid esters.

2-fluorothiophene and 3-fluorothiophene may be reacted analogously to Unterhalt, Arch.Pharm. 322, 839 (1989) to obtain the corresponding glyoxylic acid esters which may then in turn be reacted with 2- or 3-thienyl derivatives, for example, to obtain glycolic acid esters, as described above. By a suitable choice of components, symmetrically substituted dithienylglycolic acid esters may be prepared analogously.

A method analogous to benzoin condensation and benzylic acid rearrangement is also possible.

The acid chlorides required may be obtained from the acids and thionyl chloride whilst the imidazolides may be obtained from the acids and carbonyldiimidazole.

The following Examples illustrate the invention without restricting it.

EXAMPLE 1

Benzylic acid scopine ester-methobromide

a) Benzylic acid scopine ester from α-chlorodiphenyl-acetic acid chloride and scopine

26.5 g (0.1 mol) α-chlorodiphenylacetic acid chloride are added to a solution of 31.0 g (0.2 mol) of scopine in 60 ml of anhydrous pyridine at 0° C. within 50 minutes with stirring. After it has all been added the mixture is stirred for 4 hours without cooling and then left to stand for 24 hours. In order to work up the mixture the scopine hydrochloride precipitated is suction filtered. The solution separated off is evaporated down under reduced pressure, the residue is dissolved in a mixture of 600 ml of water and 15 ml of conc. hydrochloric acid and heated to about 80° C. for 10 minutes. At a temperature below 20° C., sodium carbonate is added until a pH of 9 is achieved. The benzylic acid scopine ester is extracted with methylene chloride and the extracts are dried over sodium sulphate. After evaporation and treatment with acetone, white crystals are obtained, m.p. 182°-3° C. (decomp.), yield 31.8 g (87% of theory). Elementary analysis and spectra confirm that the title compound has been obtained which can be converted in the usual way into the hydrochloride, m.p. 256° C. (decomp.; from ethanol).

b) Benzylic acid scopine ester from benzylic acid imidazolide and scopine

A suspension of 7.13 g (0.046 mol) of scopine and 3.2 g (0.0115 mol) of benzylic acid imidazolide in 50 ml of acetone is heated to boiling point. After about 10 minutes a further 9.6 g (0.0345 mol) of benzylic acid imidazolide are gradually added thereto. After the reaction has ended the mixture is cooled with ice/common salt. The crystals precipitated are suction filtered. They may be converted into the hydrochloride, m.p. 256° C. (decomp.; from ethanol). Yield 8.9 g, 53% of theory).

c) Benzylic acid scopine,ester methobromide

7.12 g (0.075 mol) of methylbromide dissolved in acetone are added to a suspension of 5.48 g (0.015 mol) of benzylic acid scopine ester in 120 ml of acetonitrile and 20 ml of carbon tetrachloride and the mixture is left to stand under a slight overpressure until the reaction has ended. The crystals precipitated are suction filtered, washed with cold acetonitrile then with diethylether and after drying (at 40° C. under reduced pressure) recrystallised from methanol/ether, m.p. 200° C. (decomp.). Elementary analysis and spectrum confirm that the desired compound has been obtained.

EXAMPLE 2

1-N-β-Fluoroethylnorscopolamine-methobromide

a) 1-N-β-Fluoroethylnorscopolamine-hydrochloride

A mixture of 16.3 (0.05 mol) of 1-norscopolamine-hydrochloride, 6.3 g (0.05 mol) of 2-bromofluoroethane, 10.6 g (0.1 mol) of sodium carbonate and 100 ml of acetonitrile is refluxed for 6 hours. Then a further 6.3 g (0.05 mol) of 2-bromofluoroethane and 5.3 g (0.05 mol) of sodium carbonate are added and the mixture is heated for a further 24 hours. Finally, 3.2 g (0.025 mol) of 2-bromofluoroethane and 2.7 g (0.025 mol) of sodium carbonate are added and the mixture is heated for a further 48 hours. It is suction filtered and the solution is concentrated by evaporation. The residue is taken up in methylene chloride, extracted with water and the methylene chloride phase is dried over sodium sulphate. After distillation of the methylene chloride an oily residue is obtained which is reacted in the usual way to form the hydrochloride. From methanol/ether 13.1 g of white crystals are obtained (70.4% of theory), m.p. 197°-8° C. (decomp.).

b) Reaction to form the methobromide

7.0 g (0.021 mol) of the amine liberated in the usual way from the hydrochloride obtained in a) are reacted in 20 ml of absolute acetonitrile with 9.9 g (0.104 mol) of methylbromide for 6 days under a slight overpressure. The crystals precipitated are recrystallised from methanol/ether. 3.9 g of white crystals, m.p. 194° C. (decomp.). Elementary analysis and spectra confirm that the title compound has been obtained.

EXAMPLE 3

Mandelic acid scopine ester methobromide

155.2 g (1.0 mol) of scopine are dissolved in 200 ml of absolute methylene chloride and 116.9 g (0.55 mol) of acetylmandelic acid chloride dissolved in 100 ml of absolute methylene chloride are added dropwise thereto (at 20° C. within 1 hour). (The acetylmandelic acid chloride is obtained from acetylmandelic acid and thionyl chloride). After one hour the scopine hydrochloride precipitated is separated off, the methylene chloride solution is extracted with water and dried.

The combined aqueous phases are made alkaline with sodium carbonate, extracted with methylene chloride and the methylene chloride phase is dried. The solvent is distilled off from the combined methylene chloride solutions. The base which remains is converted into the hydrochloride in the usual way. After recrystallisation from acetonitrile, 124.6 g (67.7% of theory) of white crystals are obtained, m.p. 207° C. (decomp.).

27.5 g (0.075 mol) of the acetyl compound thus obtained are left to stand in 110 ml of 20% hydrochloric acid for 20 hours at ambient temperature. Whilst cooling, the reaction solution is made alkaline and the mandelic acid scopine ester is extracted with methylene chloride. After drying over sodium sulphate and distillation of the solvent, the hydrochloride is prepared in the usual way. From methanol/ether, 22.5 g (92.4% of theory) of white crystals are obtained, m.p. 141°-2° C.

10.7 g (0.037 mol) of the ester liberated from the hydrochloride in the usual way are left to stand for 40 hours in acetonitrile with 17.58 g (0.185 mol) of methylbromide under a slight overpressure.

The crystals precipitated are suction filtered, washed with cold acetonitrile and recrystallised from methanol/ether. 10.0 g (70.4% of theory) of white crystals are obtained, m.p. 223° C. (decomp.).

Elementary analysis and spectra confirm that the title compound has been obtained.

EXAMPLE 4

Xanthene-9-carboxylic acid scopine ester methobromide

a) At 20° C., a solution of 11.1 g (0.11 mol) of triethylamine in 20 ml of acetone and 26.9 g (0.11 mol) of xanthene-9-carboxylic acid chloride (obtained from xanthene-9-carboxylic acid and thionyl chloride) in 80 ml of acetone are simultaneously added dropwise to a solution of 15.5 g (0.01 mol) of scopine in 50 ml of acetone at 20° C. After 4 hours a further 1.1 g (0.01 mol) of triethylamine and 2.69 (0.011 mol) of xanthene-9-carboxylic acid chloride are added. After 4 days the mixture is suction filtered and the solvent is distilled off from the solution. Sodium carbonate solution is added to the residue and extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is distilled off. From the residue, the hydrochloride of the resulting xanthene-9-carboxylic acid scopine ester is obtained in the conventional manner; white crystals from acetonitrile/ether, m.p. 223° C. (decomp.); yield 21.8 g.

b) The base is liberated in the usual way from a sufficient quantity of the hydrochloride obtained in a). 36.3 g (0.1 mol) thereof are reacted in a solution of 47.5 g (0.5 mol) of methylbromide in 49 g of acetonitrile for 24 hours under slight overpressure. The crystals obtained are suction filtered, washed with acetone/ether and recrystallised from ethanol. Yield 44.0 g (95.8% of theory), white crystals, m.p. 139° C. The crystals contain 0.5 mol of ethanol. Elementary analysis and spectra confirm the presence of the title compound.

The other compounds according to the invention may also be obtained in accordance with the Examples given above. The compounds melt with decomposition.

              TABLE 1______________________________________Compounds of formula ##STR10##No.   R.sub.1 A                     M.p.  °C.!______________________________________1     OH      3α-Tropanyl-methobromide                               275-62     OH      3α-Tropanyl-β-fluorethobromide                               205-63     H       3α-N-Ethyl-(6β,7β-Epoxy)-                               228         nortropanyl-methobromide4     H       3α-N-Propyl-(6β,7β-Epoxy)-                               206-7         nortropanyl-methobromide5     H       3α-N-Isopropyl-(6β,7β-Epoxy)-                               218         nortropanyl-methobromide6     H       3α-(6β,7β-Epoxy)-                               207         tropanyl-methobromide7     H       3α-(6,7-Dehydro)tropanyl-                               226-8         methobromide8     H       3α-Tropanyl-methobromide                               275-69     H       3α-N-Ethyl-nortropanyl-methobromide                               256-710    H       (-)-3α-N-Isopropylnortropanyl-                               256         methobromide11    H       (+)-3α-N-Isopropylnortropanyl-                               256         methobromide12    H       3α-Nortropanyl-8,1'-                               267-70         pyrrolidinium-bromide13    H       (+)-3α-Tropanyl-methobromide                               278-8114    H       (-)-3α-Tropanyl-methobromide                               278-81______________________________________

              TABLE II______________________________________Compounds of formula ##STR11##No.     R.sub.1 A                  M.p.  °C.!______________________________________1       OH      3α-N-Isopropylnortropanyl-                              258           methobromide2       OH      3α-N-β-Chlorethylnortropanyl-                              203           methobromide3       OH      3α-N-Ethylnortropanyl-                              269           methobromide4       OH      3α-Tropanyl-ethobromide                              2585       OH      3α-(6β,7β-Epoxy)tropanyl-                              200           methobromide6       OH      3α-N-Ethyl-(6β,7β-Epoxy)-                              220-1           nortropanyl-methobromide7       OH      3α-(6β,7β-Epoxy)-N-isopropyl-                              234-5           nortropanyl-methobromide8       OH      3α-N-Methylgranatanyl-                              249           methobromide9       OH      3α-N-Isopropylgranatanyl-                              219-20           methobromide10      OH      3α-(6,7-Dehydro)tropanyl-                              207-8           methobromide11      H       3α-(6,7-Dehydro)tropanyl-                              214-5           methobromide12      OH      3α-(6,7-Dehydro)-N-isopropyl-                              223           nortropanyl-methobromide13      H       3α-Nortropanyl-8,1'-                              231-2           pyrrolidinium-bromide______________________________________

              TABLE III______________________________________Compounds of formula ##STR12##No.     R.sub.1 A                  M.p.  °C.!______________________________________1       H       3α-(6β,7β-Epoxy)-tropanyl-                              213-4           methobromide2       H       3α-(6β,7β-Epoxy)-tropanyl-                              204-5           propargochloride3       H       3α-N-Ethyl-(6β,7β-Epoxy)-                              201           nortropanyl-methobromide4       H       3α-(6,7-Dehydro)tropanyl-                              238-9           methobromide5       H       3α-Tropanyl-methobromide                              203-56       OH      3α-(6β,7β-Epoxy)tropanyl-           metho-methanesulphonate______________________________________

              TABLE IV______________________________________Compounds of formula ##STR13##No.   R.sub.1 A                     M.p.  °C.!______________________________________1     H       3α-(6β,7β-Epoxy)-N-n-propyl                               213-4         nortropanyl-methobromide2     H       3α-(6β,7β-Epoxy)-N-isopropyl-                               242         nortropanyl-methobromide3     H       3α-(6β,7β-Epoxy)-N-ethyl-                               217         nortropanyl-methobromide4     H       3α-(6β,7β-Epoxy)tropanyl-                               139         methobromide (with crystal ether)5     H       3α-(6β,7β-Epoxy)tropanyl-                               128-31         ethobromide6     H       3α-Tropanyl-ethobromide                               212-37     OH      3α-N-Isopropylnortropanyl-                               229-32         metho-methanesulphonate8     H       3α-N-Isopropylnortropanyl-                               184-5         methobromide9     H       3α-(6,7-Dehydro)-N-isopropyl-                               259         nortropanyl-methobromide10    H       3α-(6,7-Dehydro)-tropanyl-                               237-8         methobromide______________________________________

              TABLE V______________________________________Compounds of formula ##STR14##No.  R.sub.1 R.sub.2 W     A            M.p.  °C.!______________________________________1    OH      H       H     3α-(6β,7β-Epoxy)-                                   223                      tropanyl-methobromide2    CH.sub.2 OH        H       H     3α-(6β,7β-Epoxy)-                                   190                      tropanyl-ethobromide3    H       Cyclo-  H     3α-(6β,7β-Epoxy)-                                   242        heptyl        tropanyl-methobromide4    H       Cyclo-  H     3α-(6β,7β-Epoxy)-                                   215-6        heptyl        tropanyl-propobromide5    --C.sub.5 H.sub.8 --            H       3α-(6β,7β-Epoxy)-                                 223-4                    tropanyl-methobromide6    CH.sub.2 OH        H       H     3α-(6β,7β-Epoxy)-N-                                   194                      (β-fluorethyl)-nor-                      tropanyl-methobromide7    CH.sub.2 OH        H       H     3α-(6β,7β-Epoxy)-N-                                   211                      (β-hydroxyethyl)-                      nortropanyl-                      methobromide8    OH      C.sub.6 H.sub.4                4-F   3α-Tropanyl-                                   220-1                      methobromide9    --C.sub.5 H.sub.8 --            H       3α-Tropanyl-                                 287-9                    methobromide10   --C.sub.5 H.sub.8 --            H       3α-N-Isopropyl-                                 263                    nortropanyl-                    methobromide11   --C.sub.6 H.sub.10 --            H       3α-N-Isopropyl-                                 261                    nortropanyl-                    methobromide12   OH      C.sub.6 H.sub.11                H     3α-(6,7-Dehydro)-                                   233-5                      tropanyl-methobromide13   H       C.sub.6 H.sub.11                3-CH.sub.3                      3α-N-Isopropyl-                                   252-4                      nortropanyl-                      methobromide14   H       C.sub.5 H.sub.9                3-CH.sub.3                      3α-Nortropanyl-                                   224-6                      8,1'-pyrrolidinium-                      bromide______________________________________

              TABLE VI______________________________________Compounds of formula ##STR15##No.    A                   R.sub.1 M.p.  °C.!______________________________________1      3α-(6β,7β-Epoxy)-tropanyl-                      H       176  methobromide.H.sub.2 O2      3α-Tropanyl-methobromide                      H3      3α-(6,7-Dehydro)-tropanyl-                      OH  methobromide4      3α-(N-β-Fluorethyl)-nortropanyl-                      H  methobromide5      3α-Tropanyl-β-fluorethobromide                      OH6      3α-(N-Isopropyl)-granatanyl-                      H  methobromide7      3α-(N-Isopropyl)-nortropanyl-                      H  methobromide8      3α-(6β,7β-Epoxy)-N-isopropyl-                      OH  nortropanyl-methobromide9      3α-(6β,7β-Epoxy)-N-ethylnor-                      OH  tropanyl-methobromide10     3α-(N-Ethyl)-nortropanyl-                      OH  methobromide11     3α-(N-Methyl)-granatanyl-                      CH.sub.3  methobromide______________________________________

              TABLE VII______________________________________Compounds of formula ##STR16##No.     A                 R.sub.1  M.p.  °C.!______________________________________1       3α-(6β,7β-Epoxy)-tropanyl-                     H   methobromide2       3α-(6,7-Dehydro)-tropanyl-                     H   methobromide3       3α-(6β,7β-Epoxy)-tropanyl-                     Methyl   methobromide4       3α-(6,7-Dehydro)-tropanyl-                     Methyl   methobromide5       3α-(6β,7β-Epoxy)-tropanyl-                     OH   methobromide6       3α-(6,7-Dehydro)-tropanyl-                     OH   methobromide______________________________________

              TABLE VIII______________________________________Compounds of formula ##STR17##No.   A                 R.sub.2    M.p.  °C.!______________________________________1     3α-(6β,7β-Epoxy)-tropanyl-                   Phenyl methobromide2     3α-(6,7-Dehydro)-tropanyl-                   Phenyl methobromide3     3α-(6β,7β-Epoxy)-tropanyl-                   Cyclopentyl methobromide4     3α-(6,7-Dehydro)-tropanyl-                   3-Thienyl methobromide5     3α-Tropanyl-methobromide                   3-Thienyl6     3α-(N-Methyl)-granatanyl-                   3-Thienyl methobromide______________________________________

              TABLE IX______________________________________Compounds of formula ##STR18##No.   A                 R.sub.2    M.p.  °C.!______________________________________1     3α-(6β,7β-Epoxy)-tropanyl-                   Phenyl methobromide2     3α-(6,7-Dehydro)-tropanyl-                   Phenyl methobromide3     3α-(6β,7β-Epoxy)-tropanyl-                   Cyclopentyl methobromide4     3α-(6,7-Dehydro)-tropanyl-                   3-Thienyl methobromide5     3α-Tropanyl-methobromide                   3-Thienyl6     3α-(N-Methyl)-granatanyl-                   3-Thienyl methobromide______________________________________

              TABLE X______________________________________Compounds of formula ##STR19##No.   A                 R.sub.1    M.p.  °C.!______________________________________1     3α-(6β,7β-Epoxy)-tropanyl-                   H methobromide2     3α-(6,7-Dehydro)-tropanyl-                   H methobromide3     3α-(6β,7β-Epoxy)-tropanyl-                   Methyl methobromide4     3α-(6,7-Dehydro)-tropanyl-                   Methyl methobromide5     3α-(6β,7β-Epoxy)-tropanyl-                   OH methobromide6     3α-(6,7-Dehydro)-tropanyl-                   OH methobromide______________________________________

              TABLE XI______________________________________Compounds of formula ##STR20##No.       A                   M.p.  °C.!______________________________________1         3α-(6β,7β-Epoxy)-tropanyl     methobromide2         3α-(6,7-Dehydro)-tropanyl-     methobromide3         3α-(6β,7β-Epoxy)-tropanyl-     ethobromide4         3α-(6,7-Dehydro)-tropanyl-     ethobromide5         3α-Tropanyl     methobromide6         3α-(N-Methyl)-granatanyl-     methobromide______________________________________

              TABLE XII______________________________________Compounds of formula ##STR21##No.       A                   M.p.  °C.!______________________________________1         3α-(6β,7β-Epoxy)-tropanyl-     methobromide2         3α-(6,7-Dehydro)-tropanyl-     methobromide3         3α-(6β,7β-Epoxy)-tropanyl-     ethobromide4         3α-(6,7-Dehydro)-tropanyl-     ethobromide5         3α-Tropanyl     methobromide6         3α-(N-Methyl)-granatanyl-     methobromide______________________________________

              TABLE XIII______________________________________Compounds of formula ##STR22##No.       A                   M.p.  °C.!______________________________________1         3α-(6β,7β-Epoxy)-tropanyl-     methobromide2         3β-(6,7-Dehydro)-tropanyl-     methobromide3         3α-(6β,7β-Epoxy)-tropanyl-     ethobromide4         3α-(6,7-Dehydro)-tropanyl-     ethobromide5         3α-Tropanyl     methobromide6         3α-(N-Methyl)-granatanyl-     methobromide______________________________________

              TABLE XIV______________________________________Quarternary compounds of formula ##STR23##No.  A                    R.sub.2   M.p.  °C.!______________________________________ 1   3α-(6β,7β-Epoxy)-tropanyl-                     2-Thienylmethobromide 2   3α-Tropanyl-methobromide                     2-Thienyl 3   3α-(6,7-Dehydro)-tropanyl-                     2-Thienylmethobromide 4   3α-(N-β-Fluorethyl)-nortropanyl-                     2-Thienylmethobromide 5   3α-Tropanyl-β-fluorethobromide                     2-Thienyl 6   3α-(N-Isopropyl)-granatanyl-                     2-Thienylmethobromide 7   3α-(N-Isopropyl)-nortropanyl-                     2-Thienylmethobromide 8   3α-(6β,7β-Epoxy)-N-isopropyl-                     2-Thienylnortropanyl-methobromide 9   3α-(6β,7β-Epoxy)-N-ethylnor-                     2-Thienyltropanyl-methobromide10   3α-(N-Ethyl)-nortropanyl-                     2-Thienylmethobromide11   3α-(N-Methyl)-granatanyl-                     2-Thienylmethobromide12   3α-(6β,7β-Epoxy)-N-β-fluoroethyl-                     2-Thienylnortropanyl-methobromide13   3α-(6β,7β-Epoxy)-N-n-propyl-                     2-Thienylnortropanyl-methobromide14   3α-Tropanyl-β-hydroxyethobromide                     2-Thienyl15   3α-(6β,7β-Epoxy)-tropanyl-                     Phenylmethobromide16   3α-Tropanyl-methobromide                     Phenyl17   3α-(N-β-Fluoroethyl)-                     Phenylnortropanyl-methobromide18   3α-(6,7-Dehydro)-tropanyl-                     Phenylmethobromide19   3α-(N-Ethyl)-nortropanyl-                     Phenylmethobromide20   3α-(N-Isopropyl)-nortropanyl-                     Phenylmethobromide21   3α-Tropanyl-ethobromide                     Phenyl22   3α-(N-Ethyl)-nortropanyl-                     Phenylethobromide23   3α-(6β,7β-Epoxy)-tropanyl-                     Phenylethobromide24   3α-Tropanyl-β-fluorthobromide                     Phenyl25   3α-Tropanyl-methobromide                     Cyclohexyl26   3α-(N-β-Fluorethyl)-nortropanyl-                     Cyclohexylmethobromide27   3α-Tropanyl-β-fluorethobromide                     Cyclohexyl28   3α-Tropanyl-methobromide                     Cyclopentyl29   3α-Tropanyl-ethobromide                     Cyclopentyl30   3α-(N-Ethyl)-nortropanyl-                     Cyclopentylmethobromide31   3α-(N-Isopropyl)-nortropanyl-                     Cyclopentylmethobromide32   3α-Tropanyl-β-fluorethobromide                     Cyclopentyl33   3α-(N-β-Fluorethyl)-nortropanyl-                     Cyclopentylmethobromide34   3α(6,7-Dehydro)-tropanyl-                     2-Thienylmetho-methanesulphonate35   3β-(6β,7β-Epoxy)-tropanyl-                     2-Thienylmethobromide36   3β-Tropanyl-methobromide                     2-Thienyl37   3β-(6,7-Dehydro)-tropanyl-                     2-Thienylmethobromide38   3α(6,7-Dehydro)-tropanyl-                     3-Thienylmethobromide39   3α-(6β,7β-Epoxy)-tropanyl-                     3-Thienylmethobromide40   (+)-Enantiomer of No. 141   (-)-Enantiomer of No. 142   3α-(6β,7β-Epoxy)tropanyl-                     2-Furylmethobromide43   3α-(6,7-Dehydro)-tropanyl-                     2-Furylmethobromide44   3α-Tropanyl-methobromide                     2-Furyl45   3α-(6β,7β-Epoxy)-tropanyl                     2-Pyridylmethobromide46   3α-(6,7-Dehydro)-tropanyl                     2-Pyridylmethobromide47   3α-Tropanyl-methobromide                     2-Pyridyl48   3α-Tropanyl-methobromide                     3-Thienyl49   3α-(6,7-Dehydro)-tropanyl                     Cyclopentylmethobromide50   3α-(6β,7β-Epoxy)-tropanyl                     Cyclohexylmethobromide51   3α-(6,7-Dehydro)-tropanyl                     Cyclohexylmethobromide52   3α-(6β,7β-Epoxy)-tropanyl                     Cyclopentylmethobromide______________________________________

              TABLE XV______________________________________Compounds of formula ##STR24##                                   M.pNo.  A                R.sub.2    R.sub.a                                    °C.!______________________________________1    3α-(6β,7β-Epoxy)-tropanyl-                 2-Thienyl  5-Methylmethobromide2    3α-(6,7-Dehydro)-tropanyl-                 2-Thienyl  5-Methylmethobromide3    3α-Tropanyl-methobromide                 2-Thienyl  5-Methyl4    3α-(6β,7β-Epoxy)-tropanyl-                 2-(5-Methyl)-                            5-Methylmethobromide     thienyl5    3α-(6,7-Dehydro)-tropanyl-                 2-(5-Methyl)-                            5-Methylmethobromide     thienyl6    3α-Tropanyl-methobromide                 2-(5-Methyl)-                            5-Methyl                 thienyl7    3α-(6β,7β-Epoxy)-tropanyl-                 2-Thienyl  5-Fluoromethobromide8    3α-(6,7-Dehydro)-tropanyl-                 2-Thienyl  5-Fluoromethobromide9    3α-Tropanyl-methobromide                 2-Thienyl  5-Fluoro10   3α-(6β,7β-Epoxy)-tropanyl-                 2-(5-Fluoro)-                            5-Fluoromethobromide     thienyl11   3α-(6,7-Dehydro)-tropanyl-                 2-(5-Fluoro)-                            5-Fluoromethobromide     thienyl12   3α-Tropanyl-methobromide                 2-(5-Fluoro)-                            5-Fluoro                 thienyl______________________________________

              TABLE XVI______________________________________Compounds of formula ##STR25##No.    A                 R.sub.2   M.p.  °C.!______________________________________1      3α-(6β,7β-Epoxy)-tropanyl                    Phenyl  methobromide2      3α-(6,7-Dehydro)-tropanyl                    Phenyl  methobromide3      3α-(6β,7β-Epoxy)-tropanyl                    3-Thienyl  methobromide4      3α-(6,7-Dehydro)-tropanyl                    3-Thienyl  methobromide5      3α-Tropanyl 3-Thienyl  methobromide6      3α-(N-Methyl)-granatanyl                    3-Thienyl  methobromide______________________________________

              TABLE XVII______________________________________Compounds of formula ##STR26##No.      A                    M.p. °C.!______________________________________ 1       3α-(6β,7β-Epoxy)-tropanyl-    methobromide 2       3α-Tropanyl-methobromide 3       3α-(6,7-Dehydro)-tropanyl-    methobromide 4       3α-(N-β-Fluorethyl)-nortropanyl-    methobromide 5       3α-Tropanyl-β-fluorethobromide 6       3α-(N-Isopropyl)-granatanyl-    methobromide 7       3α-(N-Isopropyl)-nortropanyl-    methobromide 8       3α-(6β,7β-Epoxy)-N-isopropyl-    nortropanyl-methobromide 9       3α-(6β,7β-Epoxy)-N-ethylnor-    tropanyl-methobromide10       3α-(N-Ethyl)-nortropanyl-    methobromide11       3α-(N-Methyl)-granatanyl-    methobromide12       3α-(6β,7β-Epoxy)-N-β-fluoroethyl-    nortropanyl-methobromide13       3α-(6β,7β-Epoxy)-N-n-propyl-    nortropanyl-methobromide14       3α-Tropanyl-β-hydroxyethobromide15       3α(6,7-Dehydro)-tropanyl-    metho-methanesulphonate16       3β-(6β,7β-Epoxy)-tropanyl-    methobromide17       3β-Tropanyl-methobromide18       3β-(6,7-Dehydro)-tropanyl-    methobromide______________________________________

              TABLE XVIII______________________________________Compounds of formula ##STR27##No.     A                 R.sub.1  M.p.  °C.!______________________________________1       3α-(6β,7β-Epoxy)-tropanyl                     OH   methobromide2       3α-(6,7-Dehydro)-tropanyl                     OH   methobromide3       3α-(6β,7β-Epoxy)-tropanyl                     Methyl   methobromide4       3α-(6,7-Dehydro)-tropanyl                     Methyl   methobromide5       3α-Tropanyl H   methobromide6       3α-(N-Ethyl)-nortropanyl                     H   methobromide______________________________________

              TABLE A______________________________________Compounds of formuia ##STR28##                                 Mp.  °C.!                                 Hydro-No.  A                R.sub.2   Base  chloride______________________________________ 1   3α-(6β,7β-Epoxy)-tropanyl                 2-Thienyl 149-50                                 238-41 2   3α-Tropanyl                 2-Thienyl 167-8 253 3   3α-(6,7-Dehydro)-tropanyl                 2-Thienyl 164-5 4   3α-(N-β-Fluorethyl)-                 2-Thienyl       236nortropanyl 5   3α-(N-Isopropyl)-                 2-Thienyl       232granatanyl 6   3α-(N-Isopropyl)-                 2-Thienyl       250nortropanyl 7   3α-(6β,7β-Epoxy)-N-iso-                 2-Thienyl       206propylnortropanyl 8   3α-(6β,7β-Epoxy)-N-ethyl-                 2-Thienyl       212-3nortropanyl 9   3α-(N-Ethyl)-nortropanyl                 2-Thienyl       256-710   3α-(N-Methyl)-granatanyl                 2-Thienyl       24111   3α-(6β,7β-Epoxy)-N-β-                 2-Thienyl       188-90fluorethylnortropanyl12   3α-(6β,7β-Epoxy)-N-n-                 2-Thienyl 104-6propylnortropanyl13   3α(6β,7β-Epoxy)-N-n-                 2-Thienyl       225-7butylnortropanyl14   3α-(6β,7β-Epoxy)-tropanyl                 Phenyl          246-715   3α-Tropanyl                 Phenyl          243-416   3α-(N-β-Fluoroethyl)-                 Phenyl          219-20nortropanyl17   3α-(6,7-Dehydro)-tropanyl                 Phenyl    181-318   3α-(N-Ethyl)-nortropanyl                 Phenyl          231-219   3α-(N-Isopropyl)-                 Phenyl          246-7nortropanyl20   3α-Tropanyl                 Cyclohexyl      26021   3α-(N-β-Fluoroethyl)-                 Cyclohexyl      203-4nortropanyl22   3α-(6β,7β-Epoxy)-tropanyl                 Cyclopentyl     23723   3α-Tropanyl                 Cyclopentyl     26024   3α-(N-β-Fluoroethyl)-                 Cyclopentyl     182-3nortropanyl25   3α-(N-Ethyl)-nortropanyl                 Cyclopentyl     227-826   3α-(N-Isopropyl)-                 Cyclopentyl     174-5nortropanyl27   3β-(6β,7β-Epoxy)-tropanyl                 2-Thienyl       240-228   3β-Tropanyl 2-Thienyl       217-929   3β-(6,7-Dehydro)-tropanyl                 2-Thienyl       233-530   3α-(6,7-Dehydro)-tropanyl                 3-Thienyl       247-831   3α-(6β,7β-Epoxy)-tropanyl                 3-Thienyl       242-332   3α-(6β,7β-Epoxy)-tropanyl                 2-Furyl33   3α-(6,7-Dehydro)-tropanyl                 2-Furyl34   3α-Tropanyl                 2-Furyl35   3α-Tropanyl                 2-Pyridyl36   3α-(6β,7β-Epoxy)-tropanyl                 2-Pyridyl37   3α-(6,7-Dehydro)-tropanyl                 2-Pyridyl38   3α-Tropanyl                 3-Thienyl39   3α-(6,7-Dehydro)-tropanyl                 Cyclopentyl40   3α-(6β,7β-Epoxy)-tropanyl                 Cyclohexyl41   3α-(6,7-Dehydro)-tropanyl                 Cyclohexyl______________________________________ Note: all hydrochlorides melt with decomposition.

Claims (14)

We claim:
1. A compound of formula ##STR29## wherein R is an optionally halo- or hydroxy-substituted C1-4 -alkyl group;
R' is a C1-4 -alkyl group; or
R and R' together form a C4-6 -alkylene group;
X- is an anion;
and
R1 is H, OH, CH2 OH, C1-4 -alkyl or C1-4 -alkoxy.
2. The compound according to claim 1, wherein X- is bromide.
3. The compound according to claim 1, wherein R1 is OH, CH3 or CH2 OH.
4. The compound according to claim 1, wherein R is methyl and R' is methyl, ethyl, n-propyl or i-propyl.
5. A pharmaceutical composition comprising a compound according to any one of claims 1-4 and a pharmaceutically acceptable excipient or carrier.
6. A method for treating a disease which is responsive to an anti-cholinergic agent in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of the pharmaceutical composition according to claim 5.
7. The method according to claims 6, wherein said pharmaceutical composition is administered by inhalation.
8. The method according to claim 6, wherein said pharmaceutical composition is administered intravenously or orally.
9. A method for treating a respiratory tract disease in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of the pharmaceutical composition according to claim 5.
10. The method according to claim 9, wherein said pharmaceutical composition is administered by inhalation.
11. The method according to claim 9, wherein said pharmaceutical composition is administered Intravenously or orally.
12. A method for treating sinus bradycardia in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of the pharmaceutical composition according to claim 5.
13. The method according to claim 12, wherein said pharmaceutical composition is administered by inhalation.
14. The method according to claim 12, wherein said pharmaceutical composition is administered intravenously or orally.
US08/412,408 1991-03-15 1995-03-28 Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions Expired - Lifetime US5770738A (en)

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